Attenuation of edema and infarct volume following focal cerebral ischemia by early but not delayed administration of a novel small molecule KDR kinase inhibitor.
Vascular endothelial growth factor (VEGF) may mediate increases in vascular permeability and hence plasma extravasation and edema following cerebral ischemia. To better define the role of VEGF in edema, we examined the effectiveness of a novel small molecule KDR kinase inhibitor Compound-1 in reducing edema and infarct volume following focal cerebral ischemia in studies utilizing treatment regimens initiated both pre- and post-ischemia, and with study durations of 24-72 h. Rats were subjected to 90 min of middle cerebral artery occlusion (MCAO) followed by reperfusion. Pretreatment with Compound-1 (40 mg/kg p.o.) starting 0.5h before occlusion significantly reduced infarct volume at 72 h post-MCAO (vehicle, 194.1+/-22.9 mm(3) vs. Compound-1, 127.6+/-22.8mm(3) and positive control MK-801, 104.4+/-22.6mm(3), both p<0.05 compared to vehicle control), whereas Compound-1 treatment initiated at 2h after occlusion did not affect infarct volume. Compound-1 pretreatment also significantly reduced brain water content at 24h (vehicle, 80.3+/-0.2% vs. Compound-1, 79.7+/-0.2%, p<0.05) but not at 72 h after MCAO. These results demonstrate that early pretreatment administration of a KDR kinase inhibitor elicited an early, transient decrease in edema and subsequent reduction in infarct volume, implicating VEGF as a mediator of stroke-related vascular permeability and ischemic injury.
Foster
Kelley A
KA
Department of Schizophrenia Research, Merck Research Laboratories, West Point, PA 19486, USA.
Regan
Hillary K
HK
Danziger
Andrew P
AP
Detwiler
Theodore
T
Kwon
Nancy
N
Rickert
Keith
K
Lynch
Joseph J
JJ
Regan
Christopher P
CP
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D001929:Brain Edema / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D002544:Cerebral Infarction / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D007211:Indoles / Q000737:chemistry / Q000627:therapeutic use*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D008970:Molecular Weight; D010879:Piperazines / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats; D013997:Time Factors; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
C496486:3-(5-((4-(methylsulfonyl)-1-piperazinyl)methyl)-1H-indole-2-yl)quinolin-2(1H)-one; D004791:Enzyme Inhibitors; D007211:Indoles; D010879:Piperazines; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2